Animal feed and process

ABSTRACT

AN ANIMAL FEED FOR INCREASING MEAT MILK OR EGG PRODUCTION COMPRISING A COMPOUND OF THE GROUP CONSISTING OF TRIAZOLOBENZODIAZEPINES OF THE FORMULA:   1-R1,6-(R2,R3-PHENYL),R4,R5,5,6-DIHYDRO-4-H-S-TRIAZOLO   (4,3-A)(1,4)BENZODIAZEPINE   WHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL OF 1 TO 3 CARBON ATOMS, INCLUSIVE; WHEREIN R2, R3, R4 AND R5 ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL DEFINED, AS ABOVE, FLUORINE, CHLORINE, BROMINE, NITRO, CYANO, TRIFLUOROMETHYL, ALKOXY OF 1 OT 3 CARBON ATOMS, INCLUSIVE, AMINO, ALKANOYLAMINO, IN WHICH THE ALKANOYL GROUP IS TO 3 CARBON ATOMS, INCLUSIVE, ALKYLTHIO IN WHICH THE ALKYL GROUP IS DEFINED AS ABOVE, ALKYLSULFINYL IN WHICH THE ALKYL GROUP IS DRFEFINED AS ABOVE, AND DIALKYLAMINO IN WHICH THE ALKYL GROUP IS DEFINED AS ABOVE, AND THE PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS AND N-5 OXIDES IN COMBINATION WITH THE NUTRIENT FEED.

United States Patent 3,836,662 ANIMAL FEED AND PROCESS Robert J. Collins, 7127 Winter Forest Drive, Portage, Mich. 49081 No Drawing. Filed Aug. 9, 1971, Ser. No. 170,342 The portion of the term of the patent subsequent to Sept. 17, 1991, has been disclaimed Int. Cl. A61k 27/00 US. Cl. 424-269 6 Claims ABSTRACT OF THE DISCLOSURE An animal feed for increasing meat, milk or egg production comprising a compound of the group consisting of triazolobenzodiazepines of the formula:

Formulal wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive; wherein R R R, and R are selected from the group consisting of hydrogen, alkyl defined as above, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, alkoxy of 1 to 3 carbon atoms, inclusive, amino, alkanoylamino, in which the alkanoyl group is of 1 to 3 carbon atoms, inclusive, alkylthio in which the alkyl group is defined as above, alkylsulfinyl in which the alkyl group is defined as above, and dialkylamino in which the alkyl group is defined as above, and the pharmacologically acceptable acid addition salts and N-S oxides in combination with the nutrient feed.

CROSS REFERENCE TO RELATED APPLICATIONS This application is related to copending US. application Ser. No. 114,049, filed Feb. 9, 1971, now US. Pat. No. 3,709,898, which discloses compounds of the Formula 1 and methods for their preparation.

BRIEF SUMARY OF THE INVENTION Broadly the present invention encompasses a nutritionally adequate animal feed having dispersed therein a compound of the Formula 1 in sutficient concentration to provide increasing productivity and feed efficiencies in healthy meat-producing, milk-producing or egg-laying animals. The invention also includes the process of feeding the composition to meat-producing, milk-producing or egg-laying animals.

DETAILED DESCRIPTION It has been found in recent years that meat-producing animals will gain more weight and gain it faster when various classes of compounds such as vitamins, minerals, estrogens, antibiotics, and tranquilizers are added to the diet. Although the presently available compounds are useful, new materials are still being sought that would produce weight gains more rapidly, to a greater extent, more efficiently with respect to feed intake at a lower cost and without undesirable side effects.

It is now possible by use of the present invention to obtain unexpected results in the feeding of meat-producing, milk-producing, or egg-laying animals; that is to say,

"ice

an increased rate of weight gain, an increased amount of weight gain, an increase in milk production, or increased rate of egg laying, as well as increased feed efiiciency, can be obtained by the addition of minute quantities of a compound of the Formula 1 to the animals usual nutrient feed.

Compounds of the Formula 1 can be prepared by methods disclosed in US. application Ser. No. 114,049, filed Feb. 9, 1971, now Pat. No. 3,709,898.

Unless otherwise specified, all percentages are given on a weight-to-weight basis. The pound (1b.) weights given are avoirdupois units.

Feeding of the compositions of the present invention can commence for birds shortly after hatching and in the case of mammals, during the creep-feeding period of suckling animals when they are starting on solid food and, of course, after weaning. Feeding of the compositions is continued throughout the growing period, lactation period, or egg-laying period.

The total concentration of the compound of the Formula 1 in the feed composition is determined with regard to the species of animal, age, weight, and average amount of feed consumed daily. Preferably the compound of the Formula 1 is employed in the finished feed that will supply the animal with a daily intake of from about 0.3 mg. to about 500 mg. per head per day.

The following table illustrates the range of compound of Formula 1 in milligrams daily dose per head per day for representative animals.

The foregoing dosage can generally be accomplished by providing from about 25 mg. to about 2,500 mg. of a compound of the Formula 1 per ton of finished feed.

Advantageously a compound of the Formula 1 is supplied in the form of a liquid or solid premix wherein the concentration is -2000 times greater than the desired final concentration of the: feed. For example, the compound of Formula 1 can be dissolved or suspended in a fluid vehicle such as corn oil, cottonseed oil, molasses, distillers solubles and the like to prepare a fluid premix. Alternatively, a solid premix can be prepared by mixing a compound of the Formula 1 with an edible solid diluent such as sucrose, lactose, starch, corn meal, flour, calcium carbonate, soybean meal and the like.

EXAMPLE 1 A diet for fattening lambs is prepared from the following types and amounts of ingredients:

1 Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0; Cu, 0.4 ;'I, 0.24 Zn, 0.7.

The above feed to be mixed, pelleted and offered to fattening lambs free-choice in conjunction withhay.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 0.14 gm. of 8-chloro 5,6 dihydro-1-methyl-6-phenyl-4H-s-triazolo- [4,3-a][l,4]benzodiazepine with sufficient corn meal to make one pound.

The feeding composition so prepared supplies 0.14 mg. of 8-ch1oro-5,6-dihydro-1-methyl-6-phenyl-4H-s-triazolo- [4,3][l,4]benz.odiazepine per pound or 0.31 parts per million.

The foregoing composition is usefully fed to lambs for increased rate of weight gain and improved utilization of feed.

EXAMPLE 2 A chicken feed for broilers is prepared from the following types and amounts of ingredients:

Percent Yellow corn meal 67.35 Soybean oil meal 24.00 Menhaden fish meal 6.00 Steamed bone meal 1.00 Ground limestone 1.00 Iodized salt .34 25% choline chloride .13 Vitamin B supplement (6 mg./ lb.) .10 Manganese sulfate .02 Supplemental vitamin mix 1 .06

consisting of 16.0 gm. vitamin A supplement (10 units/ mg); 36 gm. vitamin D3 supplement (15,000 units/gm); 7.1 gm. riboflavin supplement (1 gm. riboflavin per ounce); 500 mg. niacin.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 0.2 gm. 8 chloro 5,6 dihydro 1 methyl-6-phenyl-4H-s-triazolo [4,3-a][l,4]benzodiazepine with sufficient soybean mill feed to make 1 pound.

The feeding composition so prepared supplies 0.2 mg. of 8-chloro 5,6 dihydro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a] [l,4]benzodiazepine per pound or about 0.44 parts per million.

The foregoing composition is usefully fed to chickens for increased rate of weight gain and improved utilization of feed. Similarly the composition can be fed to turkeys, ducks and geese.

EXAMPLE 3 A fattening feed for 800 pound yearling cattle is prepared from the following types and amounts of ingredients:

Percent Ground ear corn 89.75 Soybean oil meal, 44% 9.0 Ground limestone 0.7 Salt 0.5 Trace mineral mixture 1 0.05

Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0; Cu, 0.4;1, 0.24 Zn, 0.7.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 0.3 gm. of 8- chloro 5,6 dihydro 1 methyl-6-phenyl-4H-s-triazolo [4,3-a] [l,4]benzodiazepine with sufficient wheat flour to make 1 pound.

The feeding composition so prepared supplies 0.3 mg. of 8-chloro-5,6-dihydro-l-methyl-6-phenyl-4H-s-triazolo [4,3-a] [l,4]benzodiazepine per pound, or about 0.66 parts per million.

Cattle are to receive the foregoing feed ad libitum together with lb. of hay per head per day and when so fed have an increased rate of Weight gain and improved utilization of feed.

4 EXAMPLE 4 A swine diet for growing hogs of 40 to pounds body weight is prepared from the following types and amounts of ingredients:

1 Contains the following percent of minerals: Mn, 12, Co, 0.08; Fe, 5.0; Cu, 0.4; I, 0.24 Zn, 0.

2 Contains 300 U.S.P. units Da/gm. and 1500 I.U.A./gm.

3 Contains per lb. riboflavin, 2000 mg. calcium pantothenate, 400 mg.; niacin, 9000 mg.; and choline chloride 10,000 mg.

* Contains 6 mg. vitamin B12 per 11).

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 0.15 gm. of 8 chloro 5,6 dihydro 1 methyl 6 phenyl 4H striaZolo[4,3-a] [l,4]benzodiazepine with sufficient ground limestone to make one pound.

The feeding composition so prepared supplies 0.15 mg. of 8-chloro-5,6-dihydro-1-methyl-6-phenyl-4H-s-triazolo- [4,3-a] [l,4]benzodiazepine per pound, or about 0.33 parts per million.

The foregoing composition is usefully fed to hogs for increased rate of weight gain and improved utilization of feed.

EXAMPLE 5 Following the procedure of the preceding Examples 1 to 4, inclusive, animal feeds are similarly prepared substituting equimolar amounts of:

8-chloro-5,6-dihydro1-methyl-6- (2,6-difluorophenyl) 4H-s-triazolo [4,3,-a] [1,4] benzodiazepine;

8-chloro-5,6-dihydrol-methyl-6- (o-chlorophenyl) -4H- s-triazolo [4,3-a] [1,4] benzodiazepine;

7-nitro-8-propyl-1-ethyl-5,6-dihydro-6- [m- (trifluoromethyl) phenyl] -4H-s-trizolo [4,3,-a] [1,4] benzodiazepine;

8-chloro-5,6-dihydro-1-ethyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine;

8-chloro-5,6-dihydro-6-phenyl-4H-s-triazolo [4,3-a]

[1,4] benzodiazepine;

8-trifluoromethyl-5,6-dihydrol-methyl-6-phenyl-4H-striazolo [4,3-a] [1,4] benzodiazepine; I

8-chloro-5,6-dihydro-1-methyl-6- (o-fluorophenyl) -4H-striazolo [4,3-a] [1,4] benzodiazepine;

7- (ethylthio)-5,6-dihydro-1-pr0pyl-6- (o-bromophenyl) 4H-s-triazolo [4,3-al] 1,4] benzodiazepine;

10- (trifluoromethyl) -5,6-dihydro-6- [p- (propionylamino) phenyl] -4H-s-triazolo [4,3-a] [1,4 benzodiazepine;

9-propoxy-5,6-dihydro-S-bromo-1-ethyl-6- [m- (ethylsulfinyl)phenyl1-4H-s-triazolol [4,3-a] [1,4] benzodiazepine;

l-methyl-S,6-dihydro-7-fiuoro-6- odiuorophenyl) -4H- s-triazolo [4,3-a] 1,4] benzodiazepine;

1-isopropyl-5,6-dihydro-6- (p-tolyl) -4H-s-triazolo [4,3-a]

[ 1,4]benzodiazepine;

1-propyl-5,6-dihydro7,10-dibromo-6-(p-chlorophenyl)- 4H-s-triazolo [4,3-a] [1,4] benzodiazepine;

1ethyl-5,6-dihydro-8-amino-6- (p-nitrophenyl) -4H-striazolo [4,3-a] 1,4]benzodiazepine;

1-isopropyl-5, 6-dihydro-8-fiuoro-6- o-cyanophenyl) 4H-s-triazolo [4,3-a] [1,4] benzodiazepine;

1-isopropyl-5,6-dihydro-9-acetamido7-chloro-6- (maminophenyl -4H-s-triazolo [4,3-a] 1,4] benzodiazepine;

7 -dimethylamino-5 ,6-dihydro-6- [omethylsulfinyl) phenyl] -4H-s-triazolo [4,3-a] 1,4] benzo diazepine;

8-(propylthio)-5,6-dihydro1-pr0pyl-6-(p-ethoxyphenyl)- 4H-s-triazolo[4,3-a] 1,4]benzodiazepine; 9-methyl-5,6-dihydro-6-(o-aminophenyl-4H-s-triaz0lo [4,3-a] [1,4] benzodiazepine; l-ethyl-S ,6-dihydro-7-nitro-8-propyl-6- [mtrifluoromethyl)pheny1]-4H-s-triazolo[4,3-a] [1,41benzodiazepine wherein R is selected from the group consisting of hydrogen, and alkyl of 1 to 3 carbon atoms, inclusive; wherein R R R and R are selected from the group consisting of hydrogen, alkyl defined as above, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, alkoxy of 1 to 3 carbon atoms, inclusive, amino, alkanoylamino, in which the alkanoyl group is of 1 to 3 carbon atoms, inclusive, alkylthio in which the alkyl group is defined as above, alklsulfinyl in which the alkyl group is defined as above, and dialkylamino in which the alkyl group is defined as above, a pharmacologically acceptable acid addition salt thereof and an N-S oxide in combination with the nutrient animal feed. 1

2. The process of claim 1 wherein the member selected is in a concentration of from 25 mg. to 2500mg. per pound of nutrient carried in the form of a premix.

3. The process of claim 1 when the member selected is in the concentration from mg. to 5000 mg. per ton of feed.

4. The process of claim 1 wherein the compound is 8- chloro 5,6 dihydro 1 methyl 6 phenyl 4H s triazolo[4,3-a] [1,4] benzodiazepine.

5. The process of claim 2 wherein the compound is 8- chloro 5,6 dihydro 1 methyl 6 phenyl 4H s-triazolo [4,3-a] [1,4] benzodiazepine.

6. The process of claim 3 wherein the compound is 8- chloro 5,6 dihydro 1 methyl 6 phenyl 4H s triazolo [4,3-a] [1,41benzodiazepine.

References Cited UNITED STATES PATENTS 3,646,055 2/ 1972 Hester, Jr. 424-269 X FOREIGN PATENTS 6916543 5/1970 Netherlands 260-308 2,012,190 9/1970 Germany 260-308 ALBERT T. MEYERS, Primary Examiner F. E. WADDELL, Assistant Examiner 

